Geminal bisphosphonates, such as for example salts of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid (risedronate) or 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronate), have been used for quite some time to treat bone diseases and for management of the metabolism of calcium.
Preparation of risedronic acid consists in reaction of 3-pyridylacetic acid with phosphoric and phosphorus trichloride with subsequent hydrolysis of resulting intermediates. The general method of this preparation of bisphosphonic acids was mentioned in JP 80-98193 (1980), JP 80-98105 (1980) of Nissan Chemical Industries and in an article W. Ploger et al., Z. Anorg. Allg. Chem., 389,119, (1972). A preparation of risedronate was published in EP 186405 (1986) of Procter & Gamble.
Bisphosphonic acids are used in the form of various non-toxic and pharmaceutically acceptable esters, alkali metal salts and salts of alkaline-earth metals and their various hydrates. The form of the substance can have a fundamental influence on its solubility and its biological availability. The preferred forms of risedronate are the sodium and calcium salts.
3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid is used mainly in the form of its mono-sodium salt (sodium risedronate). This salt, similarly as a number of other geminal bisphosphonic acids and their salts, is capable of forming hydrates. So far, anhydrous crystalline form of mono-sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate, its monohydrate and pentahemihydrate have been described in the application WO 0156983 A2 of Procter & Gamble. Of the two mentioned hydrates, only the pentahemihydrate form is thermodynamically stable. The monohydrate undergoes a spontaneous transformation to the stable pentahemihydrate.
A disadvantage of lower hydrates or anhydrous forms of monosodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate is their hygroscopicity and related instability of the content of the active substance. A decrease of the active substance content with time translates into the substance's limited storage time. Hygroscopicity can also lead to instability of a pharmaceutical preparation. For example, tablets can disintegrate under the influence of air humidity.
In case of a pharmaceutical preparation containing a mixture of the monohydrate and hemipentahydrate of monosodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate, as it is described in WO 0156983, especially the monohydrate, which is known not to be thermodynamically stable, can be a source of instability.
Solutions involving double or hermeneutically sealed packaging, or addition of a desiccant into the package, always result in additional production costs.
The present invention, which concerns new stable hydrates of the sodium salts of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid, solves this problem. These hydrates are, in addition, better soluble in diluted hydrochloric acid, which makes up stomach juices.